Abstract
We have previously reported that tocomin, a mixture high in tocotrienol content and also containing tocopherol, acutely preserves endothelial function in the presence of oxidative stress. In this study, we investigated whether tocomin treatment would preserve endothelial function in aortae isolated from rats fed a high-fat diet known to cause oxidative stress. Wistar hooded rats were fed a western diet (WD, 21% fat) or control rat chow (standard diet, 6% fat) for 12 weeks. Tocomin (40 mg/kg/day sc) or its vehicle (peanut oil) was administered for the last 4 weeks of the feeding regime. Aortae from WD rats showed an impairment of endothelium-dependent relaxation that was associated with an increased expression of the NADPH oxidase Nox2 subunit and an increase in the vascular generation of superoxide measured using L-012 chemiluminescence. The increase in vascular oxidative stress was accompanied by a decrease in basal NO release and impairment of the contribution of NO to ACh-induced relaxation. The impaired relaxation is likely contributed to by a decreased expression of eNOS, calmodulin, and phosphorylated Akt and an increase in caveolin. Tocotrienol rich tocomin, which prevented the diet-induced changes in vascular function, reduced vascular superoxide production and abolished the diet-induced changes in eNOS and other protein expression. Using selective inhibitors of nitric oxide synthase (NOS), soluble guanylate cyclase (sGC) and calcium-activated potassium (KCa) channels we demonstrated that tocomin increased NO-mediated relaxation, without affecting the contribution of endothelium-dependent hyperpolarization type relaxation to the endothelium-dependent relaxation. The beneficial actions of tocomin in this diet-induced model of obesity suggest that it may have potential to be used as a therapeutic agent to prevent vascular disease in obesity.
Highlights
The increasing incidence of obesity in western societies is clearly correlated with the incidence of cardiovascular disease [1]
We have previously reported that diabetes causes eNOS uncoupling [25] and, while we did not explore whether a high-fat diet has a similar effect in this study, obese Zucker rats are reported to have an elevated level of uncoupled eNOS [26]
There is a significant body of evidence gathered from both animal and human studies that ROS play a fundamental role in cardiovascular disease [27], including in disease associated with obesity [2]
Summary
The increasing incidence of obesity in western societies is clearly correlated with the incidence of cardiovascular disease [1]. When investigating the capacity of tocotrienols to preserve endothelial function in the presence of oxidative stress in vitro we found that when present as individual isomers α-, δ-, and γ-tocotrienol failed to demonstrate any beneficial effect [11] This lack of preservation of endotheliumdependent relaxation was despite the demonstration of effective antioxidant activity in a separate assay. This contrasted with the ability of tocomin, a palm oil extract containing a high concentration of tocotrienols and a lesser component of tocopherol, to significantly improve endothelium-dependent relaxation in the presence of oxidative stress. The aim of the present study is to investigate whether the acute protective actions of tocomin can be replicated when subcutaneously administered in vivo to rats where oxidative stress is induced by consumption of a high-fat WD that causes endothelial dysfunction
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